Process for preparing 2-methoxycarbonylmethyl-6,6-dimethyl-2-tetrahydropyran carboxylic acid

Abstract

Process for preparing 2-methoxycarbonylmethyl-6,6-dimethyl-2-tetrahydropyran carboxylic acid (I) comprising: a) Reaction of 5-bromo-2-methyl-2-pentene (III) with magnesium and then diethyloxalate to obtain ethyl-2-oxo-6-methyl-5-heptenoate (IV); b) Reaction of ethyl-2-oxo-6-methyl-5-heptenoate (IV) with an alkali amide and methyl acetate to obtain ethyl-2-methoxycarbonylmethyl-2-hydroxy-6-methyl-5-heptenoate (V); c) Reaction of ethyl-2-methoxycarbonylmethyl-2-hydroxy-6-methyl-5-heptenoate (V) with an alkali metal hydroxide to obtain the corresponding 2-carboxymethyl-2-hydroxy-6-methyl-5-heptenoic acid (VI); d) Cyclisation of 2-carboxymethyl-2-hydroxy-6-methyl-5-heptenoic acid (VI) with formic acid to give 2-carboxymethyl-6,6-dimethyl-2-tetrahydropyrancarboxylic acid (VII); e) Monoesterification of 2-carboxymethyl-6,6-dimethyl-2-tetrahydropyrancarboxylic acid (VII) to 2-methoxycarbonylmethyl-6,6-dimethyl-2-tetrahydropyran carboxylic acid (I), characterised in that in stage (e) the 2-methoxycarbonylmethyl-6,6-dimethyl-2-tetrahydropyran carboxylic acid (I) is purified by means of the formation of the corresponding salt with cyclohexylamine (IA).

1. Process for preparing 2-methoxycarbonylmethyl-6,6-dimethyl-2-tetrahydropyran carboxylic acid (I) comprising the following stages:
 a) Reacting 5-bromo-2-methyl-2-pentene (III) with magnesium and then diethyloxalate to obtain ethyl-2-oxo-6-methyl-5-heptenoate (IV); 
 b) Reacting ethyl-2-oxo-6-methyl-5-heptenoate (IV) with an alkali amide and methyl acetate to obtain ethyl-2-methoxycarbonylmethyl-2-hydroxy-6-methyl-5-heptenoate (V); 
 c) Reacting ethyl-2-methoxycarbonylmethyl-2-hydroxy-6-methyl-5-heptenoate (V) with an alkali metal hydroxide to obtain the corresponding 2-carboxymethyl-2-hydroxy-6-methyl-5-heptenoic acid (VI); 
 d) Cyclizing 2-carboxymethyl-2-hydroxy-6-methyl-5-heptenoic acid (VI) with formic acid to give 2-carboxymethyl-6,6-dimethyl-2-tetrahydropyrancarboxylic acid (VII); 
 e) Monoesterifying 2-carboxymethyl-6,6-dimethyl-2-tetrahydropyrancarboxylic acid (VII) to 2-methoxycarbonylmethyl-6,6-dimethyl-2-tetrahydropyran carboxylic acid (I), 
 wherein in stage (e) the 2-methoxycarbonylmethyl-6,6-dimethyl-2-tetrahydropyran carboxylic acid (I) is purified by means of the formation of the corresponding salt with cyclohexylamine (IA) 
 
       
         
           
           
               
               
           
         
       
     
     
       2. Process according to  claim 1 , wherein the intermediates (III), (IV), (V) and (VII) are not purified while only one purification of the intermediate (VI) is carried out at the end of stage (c) 
       
         
           
           
               
               
           
         
       
       by the formation of the corresponding cyclohexylamine salt (VIA). 
     
     
       3. Process according to  claim 2 , wherein before stage (d) said salt (VIA) is transformed into the corresponding acid (VI) for treatment with a strong mineral acid. 
     
     
       4. Process according to  claim 3 , wherein said acid is chosen between hydrochloric acid and phosphoric acid. 
     
     
       5. Process according to  claim 1 , wherein the stages (a)-(c) are carried out in polar aprotic solvent. 
     
     
       6. Process according to  claim 5 , wherein said polar aprotic solvent is tetrahydrofuran. 
     
     
       7. Process according to  claim 1 , wherein in stage (b) lithium diisopropylamide is used as an alkali amide. 
     
     
       8. Process according to  claim 1 , wherein in stage (c) the alkali hydroxide is an aqueous solution of potassium hydroxide. 
     
     
       9. Process according to  claim 1 , wherein the monoesterification in stage (e) is carried out using methanol in the presence of a strong mineral acid. 
     
     
       10. Process according to  claim 9 , wherein said strong mineral acid is concentrated sulphuric acid. 
     
     
       11. Process according to  claim 1 , wherein the salification of the product of formula (I) to the corresponding salt (IA) is carried out in a polar aprotic solvent. 
     
     
       12. Process according to  claim 11 , wherein said polar aprotic solvent is methyl acetate. 
     
     
       13. Process according to  claim 1 , wherein the 5-bromo-2-methyl-2-pentene (III) used in stage (a) is prepared by reacting cyclopropylmethylketone (II) with methylmagnesium bromide and then with a strong mineral acid in a polar aprotic solvent. 
     
     
       14. Process according to  claim 13 , wherein said strong mineral acid is sulphuric acid and the polar aprotic solvent is tetrahydrofuran. 
     
     
       15. Process according to  claim 13 , wherein the 5-bromo-2-methyl-2-pentene (III) is used as a crude product in state in stage (a). 
     
     
       16. Salt of 2-methoxycarbonylmethyl-6,6-dimethyl-2-tetrahydropyran carboxylic acid with cyclohexylamine of formula (IA)